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Exploring forbidden reactions to discover new ways of chemical synthesis

01 August 2012 Universidad de Barcelona

The complex chemical compounds, like many of the drugs currently used, are obtained through sequences of synthesis that in the case of some complex anti-tumor drugs may involve up to forty stages. Multicomponent reactions, instead, allow synthesising complex molecules in very few steps since the different chemical bonds are formed almost simultaneously in a single operation. For medicinal chemistry, these direct reactions are of great interest, although only a few have been described. Now, researchers from the Faculty of Pharmacy of the UB have discovered new multicomponent reactions providing cyclic amidines, compounds with interesting pharmacological applications. The results of this study have recently been published in the high-impact journal in chemistry Angewandte Chemie International Edition.

As part of their research, the scientific team tested a reaction that is considered to be formally forbidden, since the theoretical product that would be obtained does not comply with the stability rules that apply to organic products, and if the product was formed, their bonds would break immediately. According to the researcher who has led the study, Rodolfo Lavilla, they decided to test one of these forbidden reactions – in particular, the Povarov reaction – because the strain limit a compound can have was not well-defined, and therefore it was worth testing it. The result of the reaction was that, indeed, the forbidden compound was not formed but, instead, there was a new reaction which involves the acetonitrile used as a solvent. “The experiment could have finished here, but we decided to study whether it was a general, and therefore interesting, reaction”, states Lavilla.

The researchers observed that the reaction was consistent and that if the reactive agents were modified, a collection of chemical compounds sharing the same scaffold could be obtained. In order to explain the factors that regulate the reactivity of these new mulitcomponent reactions, Lavilla’s team collaborated with experts in computational chemistry from F. Javier Luque’s team, also from the Faculty of Pharmacy of the UB. “Calculations showed that some products obtained from the reaction were not those that could be intuitively expected, and that there exists a very fine orbital control of the reaction that regulates how the molecules take their final shape going through high-energy stages”, claims Lavilla.

 Crossing boundaries with new reactions 

Now it must be analysed whether the new molecules can have pharmacological action. Therefore, the researchers have introduced the new chemical compounds in several databases of products, making them available to the scientific community for a pharmacological exploration. As lecturer Lavilla states, “the fact of obtaining new scaffolds, as in our study, is very interesting for medicinal chemistry, as it can lead to the discovery of innovative drugs”. In this case, the new drug would have a special value because, according to the researchers, it can be obtained through a one-step multicomponent reaction, which means reducing synthesis time, and therefore, reducing its cost of production. 

The researchers indicate that the systematic exploration of uncharted reactivity space related to formally forbidden processes can be useful in the search for new multicomponent reactions, since a blocked step may enable unexpected bond formation events within the same reactant mixture. “University research must cross boundaries and experiment with reactions that are not tested yet, although from a general viewpoint they may seem nonsense because the theory says that they are forbidden reactions”, points out lecturer Lavilla. 

Also participating in the study are students Sara Preciado and Esther Vicente-García, from Lavilla’s team, from the Department of Pharmacology and Therapeutic Chemistry at the Faculty of Pharmacy of the UB and also from the Barcelona Science Park, and lecturer F. Javier Luque and the student Salomé Llabrés, from the Department of Physiochemistry at the Faculty of Pharmacy and from the Institute of Biomedicine of the UB (IBUB). Some computational studies were carried out with equipment from the Centre for Scientific and Academic Services of Catalonia (CESCA). The study has been funded by the Ministry of Science and Innovation, by the Catalan government, and by Ferrer Group.

Attached files

  • Structure of one of the compounds obtained by X-ray diffraction.

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